Structure–activity relationship of nonsecosteroidal vitamin D receptor modulators

The vitamin D receptor (VDR), a receptor for the secosteroid 1α,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], is a promising drug target in the treatment of bone and mineral disorders, cancer, autoimmune disease, infection, and cardiovascular disease. Indeed, approximately 100 nonsecosteroidal VDR modulators (VDRMs) have been developed. Analysis of X-ray crystal structures reveals: (i) nonsecosteroidal VDRMs bind to VDR in a position similar to 1,25(OH) 2 D 3 ; (ii) hydrogen bond interactions between ligands and VDR are the most important for VDR binding; (iii) hydrophobic interactions and CH–π interactions in aromatic ligands are also important for VDR binding; and (iv) exchange of C-O-C linkage to C-CH 2 -C linkage in VDRMs increases transactivation activity, probably as a result of an entropic effect of solvation/desolvation of molecules. Several VDRMs have better therapeutic efficacy when compared to 1,25(OH) 2 D 3 in experimental models of cancer and osteoporosis with less induction of hypercalcemia, a major potential adverse effect in the clinical application of VDR ligands.